Cell proliferative diseases represent a major health problem and threat worldwide. Such diseases are characterized by the single or multiple abnormal proliferation of cells, groups of cells or tissue(s). See U.S. Pat. No. 5,665,588. Cell proliferative diseases include, but are not limited to, AIDS dementia, various cancers, atherosclerosis, vitreoretinopathy, psoriasis, neurodegenerative disorders and nephropathy. See U.S. Pat. Nos. 5,639,600, 4,847,257 and 5,672,746. Dementias, or progressive mental failures, particularly present a serious worldwide health problem, both in terms of the extent of debilitation and health care costs. Dementias include non-HIV-associated dementias (such as Alzheimer's disease or AD) and HIV-associated dementia.
Macrophages are terminally differentiated cells generally incapable of further cell division. Surprisingly, macrophage proliferation has been implicated in certain serious proliferative diseases such as lymphoma, cardiovascular disease, and nephrosclerosis. U.S. Pat. No. 5,639,600. Gabrielian et al. reported the role of macrophage infiltration in traumatic proliferative vitreoretinopathy. (1994) Curr. Eye. Res. 13:1-9. McGrath et al. disclosed the involvement of clonally expanded macrophages in the induction of cancerous tumor growth and AIDS dementia. U.S. Pat. Nos. 5,639,600 and 5,580,715; see also Pulliam et al. (1997) Lancet 349:692-695; McGrath et al. (1995) J. Acquired Imm. Def. Syn. Hum. Retro. 8: 379-385; Shiramizu et al. (1994) Cancer Res. 54:2069-2072.
AD is a degenerative brain disorder clinically characterized by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a common cause of dementia in the elderly and is believed to represent the fourth most common medical cause of death in the United States. The disease is currently estimated to affect over four million Americans. To date, the disease is incurable. Various factors such as genetic predisposition, infectious agents, toxins, metals, and head trauma have all been suggested as possible mechanisms of AD neuropathology. A prevailing theory explaining the cause of AD is related to abnormal deposition of β-amyloid into plaques with associated neurofibrillary tangles. No HIV or other infectious agent has to date been associated with AD, and AD pathologic lesions are different than those associated with AIDS dementia.
Several different classes of chemical compounds have been reported that can inhibit abnormal cellular proliferation. These classes include, for example, anionic oligomers, amino 1,2,3-triazoles, valproic acid derivatives and polyamines. Cardin et al. reported that certain anionic oligomers possess antiproliferative activity. U.S. Pat. No. 5,460,807. Water soluble polyureas and polyamides with a molecular weight of less than 10,000 inhibit smooth muscle cell proliferation in culture and in vivo. Cardin et al. state that the anionic oligomers can be used in the treatment of atherosclerosis. Hupe et al. disclosed that certain triazoles are antiproliferatives. U.S. Pat. No. 4,847,257. Amino 1, 2, 3 triazoles inhibit labeled thymidine incorporation into intact pig skin and also inhibit keratinocyte proliferation. Hupe et al. state that the triazoles can be used in the treatment of psoriasis, a chronic skin disease which is characterized by hyperproliferation of the epidermis Nau et al. discovered that certain acids inhibit cell mitosis. U.S. Pat. No. 5,672,746. Derivatives of valproic acid decrease neuro-2a cell proliferation in vitro. Nau et al. state that the valproic acid derivatives can be used for the prevention and treatment of neurodegenerative disorders such as Alzheimer's disease. The treatment would be aimed at preventing the adverse effects of the disease by directly inhibiting pathologic neural cell growth.
The level of polyamines is intimately related to cell proliferation. Cellular levels of polyamines are carefully regulated by opposing synthetic and catabolic pathways. Compounds that are able to lower polyamine levels are proposed for use in the treatment of rapidly proliferating host cells such as cancer and psoriasis. A key polyamine catabolizing enzyme spermidine-spermine N1-acetyltransferase (SSAT) is among the few genes known to be inducible by the natural polyamines. Certain polyamine analogs exaggerate this response. 1,11-diethylnorspermine (DENSPM) increases SSAT mRNA levels in human melanoma cells up to 20-fold, with an increase in immunodetectable SSAT protein by 300-fold. By comparison, natural polyamine spermine is far less effective, increasing SSAT mRNA by ˜3-fold and immunodetectable protein by ˜7-fold. Fogel-Petrovic et al. (1996) Biochemistry 35:14435. Polyamine analogs also induce Z-DNA structure in vitro. This property correlates inversely with the effects on cis-diaminedichloroplatinum (II) (CDDP) cytotoxicity in human brain tumor cells. Basu et al. (1996) Anticancer Res. 16:39.
U.S. Pat. No. 5,498,522 outlines the use of SSAT as a prognostic indicator or tumor response marker. Either SSAT enzyme activity, SSAT enzyme protein, or mRNA transcripts can be measured directly, or other determinants related to SSAT induction can be measured, such as SSAT co-factor acetylCoA, and the SSAT products N1-acetylspermine and N1-acetylspermidine. Measurement of these determinants is proposed as a prognostic indicia and tumor response marker to evaluate the clinical effectiveness of anticancer agents comprising polyamine analogs. Determination is performed by collecting tumor cells by biopsy before or after treatment, and measuring the selected determinant. Hibasami et al. [(1989) Cancer Res. 49:2065] prepared an inhibitor of the natural polyamine synthetic pathway. The compound, methylglyoxal-bis(cyclopentylamidinohydrazone) (MGBCP) inhibited S-adenosylmethionine decarboxylase, spermine synthase, and spermine synthetase, competing with S-adenosylmethionine, spermidine, and putrescine, respectively. MGBCP depleted spermidine and spermine in leukemic ascites cells, and prolonged survival time of mice bearing P388 leukemia.
U.S. Pat. No. 5,541,230 (Basu et al.) indicates that spermine derivatives decrease growth in a number of human tumor cell lines, and propose their use in cancer chemotherapy. Bergeron et al. (Cancer Chemother. Pharmacol.) showed that the polyamine analogs 1,14-bis(ethylamino)-5,10-diazatetradecaone (BE-4-4-4), and 1,19-bis(ethylamino)-5,10,15-triazanonadecane (BE-4-4-4-4) directly affects growth, survival, and cell cycle progression in human brain tumor cell lines. The synthesis of BE-4-4-4-4 is disclosed in U.S. Pat. No. 5,541,230. U.S. Pat. No. 5,516,807 (Hupe et al.) claims a method for treating vascular proliferative disorders following balloon angioplasty. Bis-ethyl norspermine was found to inhibit the growth of rat aortic smooth muscle cells in culture for 8 to 15 days. It is proposed that restenosis following balloon angioplasty, graft, shunt, or athereotomy can be treated or prevented by administration of an effective amount of a polyamine, although no such experiments were performed. For other publications relating to the synthesis and use of certain polyamines, the reader is referred to EP 277,635, EP 162,413, EP 399,519, JP 85/6348, and U.S. Pat. No. 5,679,682; and to Bellevue et al. (1996) Bioorg. Med. Chem. Lett. 6:2765, and Porter et al. (1992) Falk Symposium 62:201; Marton and Pegg (1995) Ann Rev. Pharmacol. Toxicol. 35:55-91.
What is needed are methods of modulating macrophage proliferation that is associated with disease. There is also a need for methods of indicating development and/or progression of non-HIV-mediated dementias associated with macrophage proliferation.
All publications cited herein are hereby incorporated in their entirety.